The LPS-unresponsive C3H/HeJ mouse strain has been utilized to help elucidate the mechanism of action of bacterial endotoxin (LPS). These mice posses a defect in the LPS-responsiveness of their T and B lymphocytes, macrophages, and fibroblasts that is due to a mutation in a single, autosomal co-dominant gene. The biological effects of LPS are cell mediated because the interaction of LPS with lymphocytes and/or macrophages renders C3H/HeJ mice susceptible to LPS-induced lethality, immunogenicity, adjuvanticity, and tumor necrosis, as shown by the adoptive transfer of bone marrow cells from LPS-sensitive mice. C3H/HeJ mice can also be rendered LPS-sensitive by preinfection with BCG, a potent immunostimultant. Endotoxicity may be mediated by a number of LPS-induced acute phase reactants such as prostaglandins, lymphocyte activating factor, interferon, colony stimulating factor, and serum amyloid associated protein which are detectable in the sera of LPS-sensitive animals. The LPS gene may also play a vital physiological role since it appears to control the ability of macrophages to manifest LPS-induced tumor cell killing as well as the ability of macrophages to respond to LPS in vivo and in vitro with the production of physiologically relevant cytokines.